The role of Sigma-1 receptor agonist in hepatic ischemiareperfusion injury.

Abstract

Sigma-1 receptor (Sig-1R) is a ligand-operated protein that modulates activity of various proteins. It is expressed within the endoplasmic reticulum membranes of multiple organs. We examined the role of Sig-1R in hepatic ischemia-reperfusion injury (IRI). We studied IRI indicators in Sig-1R-/- mice and compared them with wild-type controls. In addition, we assessed the influence of Sig-1R agonist, fluvoxamine, on IRI in both types of animals. We found that Sig-1R-/- mice exhibited significantly decreased liver damage after hepatic IRI as compared to wild-type mice. This effect was manifested by decreased serum levels of alanine aminotransferase (AST), aspartate aminotransferase (ALT), myeloperoxidase (MPO), and supernatant level of lactate dehydrogenase (LDH), decreased endothelial glycocalyx shedding indexed by decreased serum levels of heparan sulfate and syndecan-1, slightly improved liver histology and reduced metalloproteinase-9 expression. Furthermore, in comparison to Sig-1R-/- mice, fluvoxamine significantly increased serum levels of AST, ALT, MPO, and LDH in wildtype animals in a dose-dependent manner at 6 h after IRI. Our findings demonstrate that the absence of Sig-1R provides a protective effect during hepatic IRI. Sig-1R-mediated signaling pathways may play distinct roles in IRI in different organs. The dynamic interaction between Sig-1R and other signaling molecules in different organs needs to be examined further.